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Histone demethylase

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https://www.readbyqxmd.com/read/28434780/total-chemical-synthesis-of-methylated-analogues-of-histone-3-revealed-kdm4d-as-a-potential-regulator-of-h3k79me3
#1
Muhammad Jbara, Noga Guttmann-Raviv, Suman Kumar Maity, Nabieh Ayoub, Ashraf Brik
Histone H3 methylation plays an important role in regulating gene expression. In histones in general, this mark is dynamically regulated via various demethylases, which found to control cell fate decisions as well as linked to several diseases, including neurological and cancer. Despite major progress in studying methylation mark at various positions in H3 histone proteins, less is known about the regulation of methylated H3 at Lys79. Methylation at this site is known to have direct cross-talk with monoubiquitination of histone H2B at positions Lys120 and 34, as well as with acetylated H3 at Lys9...
April 12, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28432280/small-molecules-targeting-histone-demethylase-genes-kdms-inhibit-growth-of-temozolomide-resistant-glioblastoma-cells
#2
Barbara Banelli, Antonio Daga, Alessandra Forlani, Giorgio Allemanni, Daniela Marubbi, Maria Pia Pistillo, Aldo Profumo, Massimo Romani
In glioblastoma several histone demethylase genes (KDM) are overexpressed compared to normal brain tissue and the development of Temozolomide (TMZ) resistance is accompanied by the transient further increased expression of KDM5A and other KDMs following a mechanism that we defined as "epigenetic resilience". We hypothesized that targeting KDMs may kill the cells that survive the cytotoxic therapy.We determined the effect of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells and found that both molecules are more effective against TMZ-resistant rather than native cells...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430662/histone-demethylase-jmjd3-regulates-cd11a-expression-through-changes-in-histone-h3k27-tri-methylation-levels-in-cd4-t-cells-of-patients-with-systemic-lupus-erythematosus
#3
Heng Yin, Haijing Wu, Ming Zhao, Qing Zhang, Hai Long, Siqi Fu, Qianjin Lu
Aberrant CD11a overexpression in CD4+ T cells induces T cell auto-reactivity, which is an important factor for systemic lupus erythematosus (SLE) pathogenesis. Although many studies have focused on CD11a epigenetic regulation, little is known about histone methylation. JMJD3, as a histone demethylase, is capable of specifically removing the trimethyl group from the H3K27 lysine residue, triggering target gene activation. Here, we examined the expression and function of JMJD3 in CD4+ T cells from SLE patients...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430394/structure-based-design-of-a-new-scaffold-for-cell-penetrating-peptidic-inhibitors-of-the-histone-demethylase-phf8
#4
Jerzy Dorosz, Lars Olsen, Signe Teuber Seger, Cornelia Steinhauer, Giorgos Bouras, Charlotte Helgstrand, Anders Wiuf, Michael Gajhede
The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated lysine 9 on histone H3 (H3K9me1/2) and is a transcriptional activator involved in development and cancer. Affinity and specificity of PHF8 towards H3K9me2 substrate is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated lysine 4 on histone H3. A fragment of the histone H3 tail with tri-methylated lysine 4 was used as template for structure based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays...
April 21, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28422711/melatonin-exerts-anti-oral-cancer-effect-via-suppressing-lsd1-in-patient-derived-tumor-xenograft-models
#5
Cheng-Yu Yang, Chih-Kung Lin, Chang-Huei Tsao, Cheng-Chih Hsieh, Gu-Jiun Lin, Kuo-Hsing Ma, Yi-Shing Shieh, Huey-Kang Sytwu, Yuan-Wu Chen
Aberrant activation of histone lysine-specific demethylase (LSD1) increases tumorigenicity; hence, LSD1 is considered a therapeutic target for various human cancers. Although melatonin, an endogenously produced molecule, may defend against various cancers, the precise mechanism involved in its anti-oral cancer effect remains unclear. Patient-derived tumor xenograft (PDTX) models are preclinical models that can more accurately reflect human tumor biology compared with cell line xenograft models. Here, we evaluated the anticancer activity of melatonin by using LSD1-overexpressing oral cancer PDTX models...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416760/the-histone-demethylase-kdm3a-regulates-the-transcriptional-program-of-the-androgen-receptor-in-prostate-cancer-cells
#6
Stephen Wilson, Lingling Fan, Natasha Sahgal, Jianfei Qi, Fabian V Filipp
The lysine demethylase 3A (KDM3A, JMJD1A or JHDM2A) controls transcriptional networks in a variety of biological processes such as spermatogenesis, metabolism, stem cell activity, and tumor progression. We matched transcriptomic and ChIP-Seq profiles to decipher a genome-wide regulatory network of epigenetic control by KDM3A in prostate cancer cells. ChIP-Seq experiments monitoring histone 3 lysine 9 (H3K9) methylation marks show global histone demethylation effects of KDM3A. Combined assessment of histone demethylation events and gene expression changes presented major transcriptional activation suggesting that distinct oncogenic regulators may synergize with the epigenetic patterns by KDM3A...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416745/stable-h3-peptide-was-delivered-by-gold-nanorods-to-inhibit-lsd1-activation-and-induce-human-mesenchymal-stem-cells-differentiation
#7
Xin Meng, Jianping Li, Minjuan Zheng, Lei Zuo, Chao Sun, Yongsheng Zhu, Ling Fang, Liwen Liu, Xiaodong Zhou
Recently, lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, regulates post-translational modifications and has great promise as new targets for cancer and other diseases. Moreover, the ability of LSD1 to induce the differentiation of stem cells has attracted great attention in biological fields. In this study, we designed LSD1 peptide inhibitor based on its substrate H3 peptide. Through introducing a disulfide bond to stabilize the native peptide into alpha helical structure, we get a peptide with higher cell permeability and stability compared to its parent form...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416650/epigenetic-regulator-cxxc5-recruits-dna-demethylase-tet2-to-regulate-tlr7-9-elicited-ifn-response-in-pdcs
#8
Shixin Ma, Xiaoling Wan, Zihou Deng, Lei Shi, Congfang Hao, Zhenyuan Zhou, Chun Zhou, Yiyuan Fang, Jinghua Liu, Jing Yang, Xia Chen, Tiantian Li, Aiping Zang, Shigang Yin, Bin Li, Joel Plumas, Laurence Chaperot, Xiaoming Zhang, Guoliang Xu, Lubin Jiang, Nan Shen, Sidong Xiong, Xiaoming Gao, Yan Zhang, Hui Xiao
TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs...
April 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28415746/epigenetic-up-regulation-of-ribosome-biogenesis-and-more-aggressive-phenotype-triggered-by-the-lack-of-the-histone-demethylase-jhdm1b-in-mammary-epithelial-cells
#9
Alice Galbiati, Marianna Penzo, Maria Giulia Bacalini, Carmine Onofrillo, Ania Naila Guerrieri, Paolo Garagnani, Claudio Franceschi, Davide Treré, Lorenzo Montanaro
The alterations of ribosome biogenesis and protein synthesis play a direct role in the development of tumors. The accessibility and transcription of ribosomal genes is controlled at several levels, with their epigenetic regulation being one of the most important. Here we explored the JmjC domain-containing histone demethylase 1B (JHDM1B) function in the epigenetic control of rDNA transcription. Since JHDM1B is a negative regulator of gene transcription, we focused on the effects induced by JHDM1B knock-down (KD)...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414027/arsenic-activates-the-expression-of-3%C3%AE-hsd-in-mouse-leydig-cells-through-repression-of-histone-h3k9-methylation
#10
Ambreen Alamdar, Guochen Xi, Qingyu Huang, Meiping Tian, Syed Ali Musstjab Akber Shah Eqani, Heqing Shen
Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated...
April 13, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28408473/o-glcnacylation-and-chromatin-remodeling-in-mammals-an-up-to-date-overview
#11
REVIEW
Maïté Leturcq, Tony Lefebvre, Anne-Sophie Vercoutter-Edouart
Post-translational modifications of histones and the dynamic DNA methylation cycle are finely regulated by a myriad of chromatin-binding factors and chromatin-modifying enzymes. Epigenetic modifications ensure local changes in the architecture of chromatin, thus controlling in fine the accessibility of the machinery of transcription, replication or DNA repair to the chromatin. Over the past decade, the nutrient-sensor enzyme O-GlcNAc transferase (OGT) has emerged as a modulator of chromatin remodeling. In mammals, OGT acts either directly through dynamic and reversible O-GlcNAcylation of histones and chromatin effectors, or in an indirect manner through its recruitment into chromatin-bound multiprotein complexes...
April 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28407004/epigenetically-repressing-human-cytomegalovirus-lytic-infection-and-reactivation-from-latency-in-thp-1-model-by-targeting-h3k9-and-h3k27-histone-demethylases
#12
Xin Gan, Haifeng Wang, Yanyan Yu, Wei Yi, Shanshan Zhu, En Li, Yu Liang
Human Cytomegalovirus (hCMV) infects a broad range of the population and establishes life-long latency in the infected individuals. Periodically the latently infected virus can reactivate and becomes a significant cause of morbidity and mortality in immunocompromised individuals. In latent infection, the viral genome is suppressed in a heterochromatic state and viral gene transcription is silenced. Upon reactivation, the repressive chromatin is remodeled to an active form, allowing viral lytic gene transcription, initiated by the expression of viral Immediate Early (IE) genes...
2017: PloS One
https://www.readbyqxmd.com/read/28402957/chromatin-state-dynamics-during-nk-cell-activation
#13
Yang Li, Jin Wang, Jie Yin, Xinhua Liu, Minghang Yu, Ting Li, Han Yan, Xi Wang
Studies of Natural Killer (NK) cell cytotoxicity have mainly focused on the balance of activating and inhibitory receptors, signaling transduction, calcium influx, formation of immune synapse, and cytolytic degranulation. However, little is known about the chromatin state of NK cells and the impact of its changes during target recognition. In this study, we investigate the contribution of chromatin state dynamics during NK cell activation by comprehensively analyzing a set of microarray data and two sets of Chromatin Immunoprecipitation-Sequencing (ChIP-seq) data...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28402853/structure-of-nascent-chromatin-is-essential-for-hematopoietic-lineage-specification
#14
Svetlana Petruk, Samanta A Mariani, Marco De Dominici, Patrizia Porazzi, Valentina Minieri, Jingli Cai, Lorraine Iacovitti, Neal Flomenberg, Bruno Calabretta, Alexander Mazo
The role of chromatin structure in lineage commitment of multipotent hematopoietic progenitors (HPCs) is presently unclear. We show here that CD34(+) HPCs possess a post-replicative chromatin globally devoid of the repressive histone mark H3K27me3. This H3K27-unmodified chromatin is required for recruitment of lineage-determining transcription factors (TFs) C/EBPα, PU.1, and GATA-1 to DNA just after DNA replication upon cytokine-induced myeloid or erythroid commitment. Blocking DNA replication or increasing H3K27me3 levels prevents recruitment of these TFs to DNA and suppresses cytokine-induced erythroid or myeloid differentiation...
April 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28402433/h3k4-demethylase-kdm5b-regulates-global-dynamics-of-transcription-elongation-and-alternative-splicing-in-embryonic-stem-cells
#15
Runsheng He, Benjamin L Kidder
Epigenetic regulation of chromatin plays a critical role in controlling embryonic stem (ES) cell self-renewal and pluripotency. However, the roles of histone demethylases and activating histone modifications such as trimethylated histone 3 lysine 4 (H3K4me3) in transcriptional events such as RNA polymerase II (RNAPII) elongation and alternative splicing are largely unknown. In this study, we show that KDM5B, which demethylates H3K4me3, plays an integral role in regulating RNAPII occupancy, transcriptional initiation and elongation, and alternative splicing events in ES cells...
April 10, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28401003/histone-demethylase-phf8-promotes-progression-and-metastasis-of-gastric-cancer
#16
Shuyan Li, Ao Sun, Xiuming Liang, Lin Ma, Li Shen, Tongyu Li, Lixin Zheng, Wenjing Shang, Wei Zhao, Jihui Jia
Histone demethylase plant homeodomain (PHD) finger protein 8 (PHF8) has been implicated in tumor development and malignant progression in various types of cancers. However, its potential roles in gastric cancer (GC) have not been explored. In this report, we show that PHF8 expression is upregulated in GC tissues, and the enhanced PHF8 level indicates a poor prognosis of GC patients. PHF8 knockdown reduces proliferation and metastasis of GC cells, while PHF8 overexpression has the opposite effects. Mechanistically, PHF8 interacts with β-catenin, and binds to the promoter region of vimentin, leading to the promotion of vimentin transcription...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28400174/jmj24-antagonizes-histone-h3k9-demethylase-ibm1-jmj25-function-and-interacts-with-rnai-pathways-for-gene-silencing
#17
Laure Audonnet, Yuan Shen, Dao-Xiu Zhou
Dimethylation of histone H3 lysine 9 (H3K9me2) is a heterochromatic mark linked to DNA methylation and gene repression. Removal of H3K9me2 from gene bodies by the jmjC histone demethylase IBM1/JMJ25 inhibits DNA methylation and derepresses gene expression. In this work, we analyzed the function of a closely related homolog of IBM1/JMJ25, namely JMJ24. We show that jmj24 mutations produced a number of subtle developmental defects, while affecting only a relatively small number of genes at the vegetative stage...
April 8, 2017: Gene Expression Patterns: GEP
https://www.readbyqxmd.com/read/28396876/reduced-histone-h3-lysine-9-methylation-contributes-to-the-pathogenesis-of-latent-autoimmune-diabetes-in-adults-via-regulation-of-suv39h2-and-kdm4c
#18
Xi-Yu Liu, Hong Li
Aims. Latent autoimmune diabetes in adults (LADA) is an autoimmune disease of which the mechanism is not clear. Emerging evidence suggests that histone methylation contributes to autoimmunity. Methods. Blood CD4(+) T lymphocytes from 26 LADA patients and 26 healthy controls were isolated to detect histone H3 lysine 4 and H3 lysine 9 methylation status. Results. Reduced global H3 lysine 9 methylation was observed in LADA patients' CD4(+) T lymphocytes, compared to healthy controls (P < 0.05). H3 lysine 4 methylation was not statistically different...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/28384648/regulation-of-the-jmjd3-kdm6b-histone-demethylase-in-glioblastoma-stem-cells-by-stat3
#19
Maureen M Sherry-Lynes, Sejuti Sengupta, Shreya Kulkarni, Brent H Cochran
The growth factor and cytokine regulated transcription factor STAT3 is required for the self-renewal of several stem cell types including tumor stem cells from glioblastoma. Here we show that STAT3 inhibition leads to the upregulation of the histone H3K27me2/3 demethylase Jmjd3 (KDM6B), which can reverse polycomb complex-mediated repression of tissue specific genes. STAT3 binds to the Jmjd3 promoter, suggesting that Jmjd3 is a direct target of STAT3. Overexpression of Jmjd3 slows glioblastoma stem cell growth and neurosphere formation, whereas knockdown of Jmjd3 rescues the STAT3 inhibitor-induced neurosphere formation defect...
2017: PloS One
https://www.readbyqxmd.com/read/28382930/highly-selective-inhibition-of-histone-demethylases-by-de-novo-macrocyclic-peptides
#20
Akane Kawamura, Martin Münzel, Tatsuya Kojima, Clarence Yapp, Bhaskar Bhushan, Yuki Goto, Anthony Tumber, Takayuki Katoh, Oliver N F King, Toby Passioura, Louise J Walport, Stephanie B Hatch, Sarah Madden, Susanne Müller, Paul E Brennan, Rasheduzzaman Chowdhury, Richard J Hopkinson, Hiroaki Suga, Christopher J Schofield
The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates...
April 6, 2017: Nature Communications
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